Sarah Attwood, BSc
Director of Client Services
Abstract: Institutional review boards (IRBs) continue to be overburdened with
reports not required by federal regulations. It is important to understand the
difference between what the regulations require and what has become an industry
standard. Additionally, clinical research sites are often confused about
reporting requirements and err on the side of conservatism by over-reporting. By
clearly identifying regulatory requirements, the clinical research industry may
become more efficient and eliminate unnecessary work for sites as well as IRBs.
Study sites are over-reporting adverse events (AEs) and serious adverse events (SAEs) for studies conducted under Investigational New Drug (IND) applications. IRBs are required by the U.S. Food and Drug Administration (FDA) and the Office of Human Research Protections (OHRP) within the Department of Health and Human Services to review “unanticipated problems involving risks to participants or others.”
IntegReview IRB is a central IRB that reviews many protocols each year, just as institutional IRBs do. In 2016, IntegReview IRB saw an increase in the number of IND safety reports and a slight decrease in SAE reports. The reason for these changes is unknown. IntegReview IRB is seeing about a four-fold increase in IND safety reports, which is far above the increase in business.
IRBs receive many IND safety reports that are not related to the current protocol at the clinical researchsite. The reports could be about something that is happening in Asia or Europe, a different use of the drug, or a different research project. These reports must be processed, even though they are not under the jurisdiction of the IRB for the current study, creating information overload.
While protecting research subjects is paramount, sending IND safety reports to IRBs for issues that do not meet the definition of an unanticipated problem does not accomplish this. Sponsors often send IND safety reports that are not related to the current study to investigators and instruct the investigators to submit them to the IRB. Some IND safety reports only have part of the necessary information because the situation is evolving.
The OHRP defines an unanticipated problem as any outcome or experience that meets three criteria (Table 1). The problem must be unexpected given the nature of the protocol and the study population, related or possibly related to the participation in the research (any reasonable possibility), and suggest that the research places research subjects or other people at a greater risk of harm. The harm is anything that was not previously known or recognized. It could be psychological, social, economic, or physical.
Examples of unanticipated problems include information that changes the risk/benefit ratio of the research and an unanticipated adverse device effect. Perhaps something happened after implanting the device in a device study that was not in the protocol or other information provided to the IRB. This problem is unanticipated. Another example is the imminent threat of a reportable event that has not yet occurred, such as a breach of confidentiality. This could occur if an investigator accidentally leaves a laptop with study data in a taxi. Another example is a dosing error, such as giving a subject a dose that is 10 times the study dose. An unanticipated problem may not cause an AE right away. In order to be an unanticipated problem, however, the problem must also meet the other criteria of being related or possibly related to the research and increase the risk of harm.
There are four reasons for over-reporting: The protocol design, standard operating procedures, protection, and lack of training/tools. Protocols often specify that SAEs must be reported to the sponsor and the IRB. Standard operating procedures may also specify that IND safety issues be reported to the IRB. No one will ignore requirements stated in a protocol or standard operating procedure. Clinical research professionals must protect subjects; however, in today’s litigious society, clinical research professionals also want to protect themselves, which results in over-reporting.
Lack of training and tools is the last reason for over-reporting. The OHRP has useful decision trees on its website for what should be reported. Different IRBs have different reporting requirements. Knowing the IRB’s requirements will help stop over-reporting of IND safety issues.
Change is not easy. People tend to go back to what they know and are used to doing. One solution to over-reporting is education to ensure that all clinical research sites and investigators, as well as sponsors and contract research organizations, are informed about what needs to be reported. Standard operating procedures should also be updated to reflect current federal regulations.
Table 2 highlights FDA regulations for sponsors, investigators, and IRBs. The regulations require sponsors to ensure “that FDA and all participating investigators are promptly informed of significant new adverse effects or risks with respect to the drug.” For IND safety reports, the sponsor must:
“Promptly review all information relevant to the safety of the drug obtained or otherwise received by the sponsor from foreign or domestic sources, including information derived from any clinical or epidemiological investigations.”
Sponsors are specifically required to notify all participating investigators (and FDA) in a written IND safety report of “any adverse experience associated with the use of the drug that is both serious and unexpected” and “any finding from tests in laboratory animals that suggests a significant risk for human subjects” (§ 312.32(c)(1)(i)(A),(B)). And, more generally, sponsors are required to “keep each participating investigator informed of new observations discovered by or reported to the sponsor on the drug, particularly with respect to adverse effects and safe use” (§ 312.55(b)).
There is no federal regulation requiring sponsors or investigators to report IND safety issues to the IRB.
An investigator must immediately report to the sponsor any SAE whether or not it is considered drug-related, including those listed in the protocol or investigators brochure. The report must include an assessment of whether there is a reasonable possibility that the drug caused the event. FDA regulations also require the investigator to report to the IRB any changes in research activity and unanticipated problems involving risk to human subjects or others. There is no federal regulation that states that the investigator should send IND safety reports to an IRB.
IRBs are required to follow written procedures to ensure prompt reporting to the IRB, the FDA, and appropriate institutional officials of any unanticipated problems involving risks to human subjects or others and any instance of serious or continuing non-compliance. The regulations do not mention reporting IND safety issues to an IRB.
The FDA, OHRP, and the International Conference on Harmonisation (ICH) all have guidance documents related to safety reporting. Two FDA guidance documents are:
- Guidance for Clinical Investigators, Sponsors, and IRBs: Adverse Event Reporting to IRBs – Improving Human Subject Protection (January 2009)
- Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies (December 2012).
Investigators are required to report promptly to the IRB all unanticipated problems involving risks to human subjects or others, including adverse events that should be considered unanticipated problems. An AE is considered an unanticipated problem, which needs to be reported to the IRB, only if it is
- serious, and
- would have implications for the conduct of the study.
The guidance document uses the example of a research subject who is having liver issues such as hepatic necrosis. The subject never had the underlying disease before, and the protocol and investigators brochure do not mention liver issues. This AE is unexpected and serious, thus, it must be reported to the IRB.
The FDA guidance documents have examples of corrective actions for unanticipated problems. The unanticipated problem might require a significant and usually safety-related change in the protocol such as revising the inclusion/exclusion criteria. Other corrective actions for unanticipated problems include new monitoring requirements, revisions to the informed consent form, or revisions to the investigators brochure. In some cases, the study might be suspended.
The OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events (January 2007) is very similar to the FDA regulations. Reporting is required for any incident, experience, or outcome that meets all of the following criteria:
- Unexpected (in terms of nature, severity, or frequency) given the procedures and characteristics of the subject
- Related or possibly related to participation in the research
- Places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.
In November 2016, the ICH released the Integrated Addendum to ICH E6 (R1): Guideline for Good Clinical Practice E6 R2. The revision was necessary due to the increasing complexity of research studies because the original guideline was published in 1996. The revisions do not affect IRBs or safety reporting. They focus on quality management, clinical monitoring, and so forth.
ICHE6 GCP states that the sponsor is responsible for the ongoing safety evaluation of the investigational product(s). The sponsor must promptly notify investigators, institutions, and the regulatory authority(ies) about findings that could adversely affect the safety of subjects, impact the conduct of the trial, or alter the IRB’s approval/favorable opinion to continue the trial. The sponsor must expedite the reporting of all serious and unexpected adverse drug reactions to all concerned investigator(s)/institutions(s), to the IRB(s)/institutional ethics committee(s) where required, and to the regulatory authority(ies).
The investigator must report all SAEs immediately to the sponsor except for those SAEs that the protocol or other document (for example, the investigators brochure) identifies as not needing immediate reporting. The investigator should also report unexpected serious adverse drug reactions to the regulatory authority(ies), the IRB, and the institutional ethics committee. ICHE6 GCP does not mention safety reporting to IRBs.
The Burden of Over-reporting
Over-reporting of IND safety issues is a burden on more than clinical research site personnel time. There are costs associated with over-reporting, and it is also a burden on IRB time. In 2015, the Clinical Trials Transformation Initiative (CTTI) conducted a study comprised of an online survey of in-depth interviews with 47 principal investigators and 154 study staff. CTTI develops and drives adoption of practices that will increase the quality and efficiency of clinical trials. It comprises more than 80 organizations from across the clinical trial enterprise, including representatives of government agencies, industry representatives, patient advocacy groups, professional societies, investigator groups, academic institutions, and other interested parties.
The participating principal investigators and study staff had an average of 10 years of clinical trial experience. Many were working on 30 studies concurrently.1
The survey assessed the FDA’s Final Rule: Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans (March 2011) to determine whether IND safety reporting by clinical research sites had decreased. Table 3 highlights survey results, including the estimated number of IND safety reports received per month. Over 90% of the clinical research sites received 10 or more safety reports per month. More principal investigators than study staff (coordinators) estimated that it took more than 20 hours per month to manage IND safety reports. Overall, more than 50% of both principal investigators and study staff estimated that more than 10 hours per month were spent managing IND safety reports. There is a cost associated with this time.
Another question asked about reasons for not reporting safety issues. The most common reason was that the issue did not meet the IRB’s reporting requirements. Other answers were that the issue did not comply with the FDA rules and workload.
Since the rule became effective, the number of reports has not decreased. CTTI reviewed the findings and concluded that IND safety reporting still posed a substantial burden on clinical research sites without enhancing the safety of research subjects. Respondents favored a centralized overall platform-independent system for dissemination of aggregate safety data, with email alerts to investigators. This would reduce the reporting burden on clinical research sites by facilitating only necessary reporting.
In 2015, Jonathon Jarrod and Sean Khozin at the FDA reviewed a random sampling of 160 expedited safety reports. They concluded that 86% of the reports were uninformative or did not meet the criteria for submission. Jarrod and Khozin wrote:
“More than half (54%) were expedited reports of expected adverse events, listed in the product labeling of the investigator’s brochure … of the 38 expedited safety reports that met all three criteria, 16 (42%) were anticipated.”1
The FDA’s efforts not only failed to improve the quality of the reports, but it also failed to reduce the sheer number of expedited reports submitted each year. The main barriers to improving the quality of expedited reports are a “lack of international harmonization for reporting rules, liability risks, and a lack of clarity of threshold rules for aggregate reporting.” The FDA is looking into ways to modernize expedited safety reporting, and has called on sponsors to work to identify and address the underlying issues that result in over-reporting.1
The Cost of Over-reporting
As mentioned, over-reporting to the IRB is costly for clinical research sites. Say, for example, that a study coordinator spends five minutes submitting the IND safety report to the IRB and another five minutes obtaining the principal investigator’s signature and putting the report in the site file. That is 10 minutes per IND safety report. If there are 10 IND safety reports per month, each study coordinator is spending 100 minutes, or 1.5 hours, per month on IND safety reports, most of which are not relevant to the study being conducted at the clinical research site. If a study is using a central private IRB that charges $25 (or more) per IND safety report and these reports are not unanticipated problems and thus, are not required to be submitted to the IRB, then you see how this affects a project’s budget. If there are 100 clinical research sites participating in a study and each submits two reports each month, the cost of reporting could be $5,000 per month.
Instead of handling unnecessary IND safety reports, study coordinators could be working on many other important tasks such as study visits, recruitment, data entry, and answering queries. Monitors could be spending their time reviewing studies for non-compliance instead of reviewing IND safety reports. IRBs must review every IND safety report that they receive. This requires resources, including a scientific reviewer and the time and cost for follow-up if necessary. Often, IRBs do not receive all of the information or the context for the safety reports.
It will take time to identify solutions (Table 4). Clinical research professionals should discuss IND safety reporting for each protocol with the IRB. For example, if the sponsor’s standard operating procedure requires reporting of any event to the IRB, it may be possible to submit these reports to the IRB on a monthly basis or in batches. Another possible solution is to report only risks that were previously unknown or unexpected in type, severity, or frequency of occurrence.
The IRB’s role is to protect the safety, welfare, and rights of subjects; however, over-reporting does not enhance these goals. Educating sponsors, contract research organizations, and clinical research sites about appropriate IND safety reporting is crucial. Reporting only unanticipated problems to the IRB does protect the safety, welfare, and rights of subjects, and it does not compromise the integrity of the study. Appropriate IND safety reporting improves efficiencies. Following the regulatory requirements will decrease study budgets, reduce IRB processing and reviews, save time for study coordinators and principal investigators, and save money for clinical research sites.